CN102911256B - Polypeptides complexe of a kind of radio-labeling and its preparation method and application - Google Patents
Polypeptides complexe of a kind of radio-labeling and its preparation method and application Download PDFInfo
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供一种放射性核素标记的RGD多肽配合物，所述的配合物结构中，放射性核素选自64Cu、68Ga、111In、62Cu、67Cu、67Ga、86Y、89Zr或18F，配体为结构如式（1）所示的含有RGD结构单元的配体化合物。本发明的配合物具有更强的配体稳定性，其配体与整合素αvβ3受体的亲和力更强，具有高靶/非靶比值的优点。本发明还提供所述配合物的制备方法，以及其在制备肿瘤显像剂中的应用。 The present invention provides a radionuclide-labeled RGD polypeptide complex. In the complex structure, the radionuclide is selected from 64 Cu, 68 Ga, 111 In, 62 Cu, 67 Cu, 67 Ga, 86 Y, 89 Zr or 18 F, the ligand is a ligand compound containing RGD structural units with the structure shown in formula (1). The complex of the invention has stronger ligand stability, stronger affinity between the ligand and the integrin α v β 3 receptor, and has the advantage of high target/non-target ratio. The invention also provides a preparation method of the complex and its application in the preparation of tumor imaging agents.
Description
Technical field
The present invention relates to a kind of radioactivity title complex, its preparation method and described title complex are as the application of tumor developer.
Background technology
Incidence trend according to current cancer, the year two thousand twenty whole world cancer morbidity will than increasing by 50% now, and the annual newly-increased cancer patients's number in the whole world will reach 1,500 ten thousand people (World Health Organization (WHO) delivers " report of world's cancer " in the recent period). Discovery and early treatment reduce the most effective method of cancer mortality early. Implement the generaI investigation system to intestinal cancer, cervical cancer, mammary cancer etc., the cancer mortality number in the whole world can be made to reduce 1/3rd. At present in developing country, the cancer patients of 80% was just found in ill late period.
Although the precise mechanism that cancer occurs is still unclear at present, if but can in early days cancer be diagnosed, and take operation as early as possible, radiation or chemotherapy (or combination of this several method), most of tumour patient is the possibility having survival. therefore in order to cancer cells spread before to patient, we need the technology developing energy Sensitive Detection cancer, the current formation method for cancer diagnosis mainly contains: X-ray CT, ultrasonic (CS), Magnetic resonance imaging (MRI) and nuclear medicine SPECT/PET. US and MRI technique may be used for the dissection and analysis of noumenal tumour, but the shortcoming of these technology is: they can not detect the Biochemical changes of tumor tissues on a molecular scale, because MRI and CT technology needs to form very strong contrast containing a lot of contrast agents with also healthy tissues in tumor tissues, another shortcoming of these technology is that they are for frequently-occurring tumour (such as mammary cancer, carcinoma of gallbladder, lung cancer and prostate cancer) specificity and susceptibility poor, therefore we need the radiotracer developing a kind of new tumour-specific badly, it not only can be used in the early diagnosis of tumour, and the reaction for pharmacological agent of the growth of tumour and tumour can be monitored.
New vessel is to the growth of tumour and shifts most important, it does not have new vasculogenesis tumour can no longer continue growth after growing to a certain size. One of molecular marker relevant to new vessel is integrin alphav��3Acceptor, it has at neovascular endothelium cell surface and some tumor cell surface highly expresses, and does not express in the blood vessel existed and healthy tissues or express very low. Therefore integrin alphav��3Acceptor can as the important target spot of early diagnosis of tumor. Research shows, containing RGD(Arg-Gly-Asp, arginine-glycine-aspartic acid) part of sequence and integrin alphav��3Acceptor has high affinity and specificity. Therefore utilize radioisotope labeling containing RGD structure compound can as identification protein alphav��3Radiotracer, it is not only possible to for the early treatment of tumour, and can detect tumour development (occur in local or spread) and for the reaction of pharmacological agent.
The tracer agent containing RGD sequence of the radioisotope labeling reported at present has multiple, nucleic used comprise iodine-125 (125I), technetium-99m (99MTc), Value linear (18F), copper-64 (64Cu) and gallium-68 (68Etc., Ga) RGD part used comprises monomer, dimer, the tetramer and polymer.
From the selection of part, the biological activity of monomer is lower, show as that receptor affinity is not high, tumor uptake is on the low side and development background higher, affect the final development quality of tracer agent. The biological property of dimer, the tetramer and polymer is become better and better, but synthesis cost can sharply increase, and therefore considers and selects dimer the most suitable. In dimer distance between two RGD unit can the activity of remarkably influenced part, the stability of part is also important parameter in addition. The spacing that current existing RGD dimer also exists two unit not to be best, stability be not best problem, it is therefore desirable to invent novel rgd peptide dimer, make in dimer molecule the stability that the distance between two RGD monomers is suitable, strengthen part, to improve part and integrin alphav��3The avidity of acceptor, increases the picked-up of tumour, obtains better diagnosis effect.
Select from nucleic, it is applicable to the development nucleic Value linear of PET (positron emission tomography imaging art), copper-64 and gallium-68 and there is advantage.18F is positron radionuclide the most conventional in the world at present, its core excellent property, atomic radius is little does not almost affect mark character, launches that positron energy is low can better spatial resolution, when transformation period is applicable to mark and dispensing, and accelerator is convenient for production to be easy to get.18F is radionuclide the most frequently used during PET development checks, in the PET imaging medicament of current whole world application,18F tagged compound accounts for more than 90%, extensively for the inspection of the multiple internal organs illness such as the heart, brain, bone, tumour.
At present, copper-64 and gallium-68 are metal ion, it is possible to generate marker ligand compound by the coordination reaction of simplicity,18F marker all utilizes automatic DNA synthesizer DNA to prepare through complicated mark process, length consuming time, cost height. For this reason, this project adopt NOTA be coordinating group, be connected with RGD dimer by certain way, both may be used for the mark of copper-64 and gallium-68, it is also possible to by with Al18F coordination obtains18The RGD developer of F mark. Particularly for18F marks, it is possible to greatly simplify mark process, it is to increase product rate. Briefly, first RGD dimer prepared product is developed to froze-dried kit, adds before use18The solution of F mark obtains after mixing after simple purification18The injection formulations of F mark, in conjunction with PET imaging technique for integrating fibroin ��v��3The diagnosing tumor highly expressed or therapeutic evaluation.
Summary of the invention
The primary and foremost purpose of the present invention is to provide the RGD title complex of a kind of new radio-labeling with premium properties, and this title complex has stronger ligands stabilize, its part and integrin alphav��3The avidity of acceptor is stronger, has the advantage of high target/non-target ratio.
Another object of the present invention is to provide the preparation method of the RGD title complex of described new radio-labeling, the method preparation is simple, and cost is low.
Another object of the present invention is to provide described title complex in the application preparing in tumor developer.
The object of the present invention can be achieved through the following technical solutions:
First, the present invention provides a kind of ligand compound (compound 1) containing RGD structural unit, and structure is such as formula shown in (1):
In ligand compound 1 of the present invention, shown in (1), RGD structure is the dimer of RGD cyclic peptide, and described dimer is connected and obtain by specific chemical species by RGD monomer, is then connected on described dimer by chelation group NOTA.
Secondly, the present invention also provides the preparation method of the described ligand compound containing RGD structural unit, comprises the following steps:
1) preparation of PEG4-c (RGDfK)
1.1) by the Boc (t-Butylcarbamate of 0.1 ~ 1.5mmol, tertiary butoxy carbonyl) the PEG4(polyoxyethylene glycol protected) it is dissolved in 0.5 ~ 5mLDMF (dimethyl formamide), add 0.2 ~ 2.0mmolN-N-Hydroxysuccinimide (NHS) and 0.2 ~ 2.0mmol dicyclohexylcarbodiimide (DCC), at room temperature react 1 ~ 5 hour, obtain mixed reaction solution;
1.2) the RGDfK cyclic peptide monomer of 0.1 ~ 1.5mmol is joined step 1.1) in the mixed reaction solution that obtains, regulate pH to 8 ~ 9, room temperature reaction 8 ~ 12 hours, and then add the ammonium acetate buffer termination reaction of the 0.5mol/L concentration of 2 ~ 8mL, obtain product B oc-PEG4-c (RGDfK);
1.3) deprotection: 0.5 ~ 3mL trifluoroacetic acid (TFA) is added 1.5 ~ 10mg step 1.2) in the Boc-PEG4-c (RGDfK) that obtains, room temperature reaction 20 ~ 60 minutes, sloughs Boc blocking group, obtains PEG4-c (RGDfK);
2) E [PEG4-c (RGDfK)]2Preparation
2.1) L-glutamic acid (E) protected by the Boc of 1 ~ 2mmol is dissolved in 3 ~ 5mLDMF; add the DCC of the NHS and 2 ~ 6mmol of 2 ~ 6mmol; room temperature reaction 8 ~ 12 hours; the crude product obtained dissolves with 1 ~ 3mL methylene dichloride; filter; filtrate is slowly added drop-wise in the ether of 20 ~ 50mL, precipitates out and is precipitated as expection product B oc-E (OSu)2;
2.2) by 0.01 ~ 0.05mmol step 2.1) Boc-E (OSu) that obtains2Being dissolved in DMF with after PEG4-c (RGDfK) mixing that 0.02 ~ 0.1mmol step 1) obtains, regulate pH value of solution to 8 ~ 9, room temperature reaction obtains Boc-E [PEG4-c (RGDfK)] for 8 ~ 12 hours2, remove protecting group with TFA, obtain E [PEG4-c (RGDfK)]2;
3) NOTA-E [PEG4-c (RGDfK)]2The preparation of (compound 1)
By the NOTA-NHS of 0.01 ~ 0.1mmol with containing 0.01 ~ 0.1mmol step 2) E [PEG4-c (RGDfK)] that obtains2DMSO and the solution mixing that mixes with 2:1 volume ratio of water, regulate pH to 8 ~ 9, room temperature reaction 8 ~ 12 hours, with proper amount of acetic acid solution termination reaction, obtains compound 1:NOTA-E [PEG4-c (RGDfK)]2��
On this basis, the present invention provides the rgd peptide title complex of a kind of radioisotope labeling, and in described complex structure, radionuclide can be selected from64Cu��68Ga��111In��62Cu��67Cu��67Ga��86Y��89Zr or18F, part is the ligand compound 1 containing RGD structural unit of the present invention.
In the rgd peptide title complex of the preferred radioisotope labeling of the present invention, radionuclide is18F��64Cu or68Ga��
And, the present invention also provides the method for the RGD title complex of the radio-labeling described in preparation, and namely radionuclide and RGD part (compound 1) react the RGD title complex preparing described radio-labeling under proper condition. Preferred preparation method is following wet method or lyophilization:
A) wet method, comprises the following steps:
A1) described compound 1 and aluminum chloride are dissolved in buffered soln or deionized water respectively, then two kinds of solution are mixed so that it is in the weight ratio of compound 1 and aluminum chloride be 20 ~ 100:1;
A2) in step a1) mixing solutions that obtains adds acetonitrile or ethanol, and fresh obtained radionuclide deionized water solution, airtight 70 ~ 120 �� of C react 5 ~ 30min, cooling;
A3) by step a2) cooling after solution thin up after through separation and purification, remove unreacted radionuclide ion, obtain the RGD title complex of radioisotope labeling with ethanol solution hydrochloride or ethanolic soln drip washing.
B) lyophilization, comprises the following steps:
B1) described compound 1 and aluminum chloride are dissolved in buffered soln or deionized water respectively, then two kinds of solution are mixed so that it is in the weight ratio of compound 1 and aluminum chloride be 20 ~ 100:1; By mixing solutions after sterile filtration, being sub-packed in container, sealing of jumping a queue after lyophilize, obtains froze-dried kit;
B2) to step b1) the medicine box that obtains adds acetic acid solution or buffered soln dissolves, then add acetonitrile or ethanol, and fresh obtained radionuclide deionized water solution, airtight 70 ~ 120 �� of C react 5 ~ 30min, cooling;
B3) step b2) after the reaction solution thin up that obtains, through separation and purification, remove unreacted radionuclide ion, obtain the title complex of radioisotope labeling with ethanol solution hydrochloride or ethanolic soln drip washing.
In aforesaid method, described radionuclide is nuclear medicine image part, except18Outside F, it is also possible to for64Cu��68Ga��111In��62Cu��67Cu��67Ga��86Y and89Zr etc.; Described buffered soln is the material of stable reacting liquid pH value, it is possible to be acetate, lactic acid salt, tartrate, malate, maleate, succinate, ascorbate salt, carbonate or phosphoric acid salt and their mixture etc.
The chemical substance used in the above-mentioned synthesis step of the present invention is commercial goods.
In addition, the present invention also provides the rgd peptide title complex of described radioisotope labeling in the application preparing in tumor developer.
In described application, it is preferable that the rgd peptide complex preparation of described radioisotope labeling is become the tumor developer liquid injection of water white transparency.
The useful effect of the present invention:
1. the present invention introduces NOTA as coordinating group in RGD part, it provides more simple Radiolabelling method. Can effectively shortening the mark time and improve mark product rate, but also easily be automated synthesis, this is for extremely important transformation period shorter radionuclide, advantageously in commercial applications and the clinical expansion of radioactively labelled substance.
2. the title complex that RGD part of the present invention and radionuclide are formed is more stable, is conducive to improving the target picked-up of marker ligand compound, and avoids radioactivity degradation production to the impact of development quality.
3. the present invention introduces two PEG4 groups between two RGD monomers, the flexibility between RGD monomer can be increased, increase the probability that each RGD monomer is combined with integrin receptor, strengthen the avidity between part and acceptor further, improve the tumor uptake of radiolabeled complexes, reach better diagnosis effect.
4. the present invention introduces PEG4 group in part the characteristic of PEG can also be utilized to improve the pharmacokinetic property of marker ligand compound, accelerate the removing speed of tracer agent in non-target background, increase target/non-target ratio, make development more clear, reach better diagnosis effect by improving development quality.
Accompanying drawing explanation
Fig. 1 is18The HPLC analysis chart of F marker ligand compound.
Fig. 2 is different compound and the acceptor �� of RGD containing peptidesv��3Competitive binding assay result.
Fig. 3 be [18F] structural representation of AlF-NOTA-PRGD2 and HPLC analysis chart.
Fig. 4 is18The bio distribution result of F marker ligand compound in lotus U87MG knurl nude mouse.
Fig. 5 is18F marks different time PET development figure (wherein NOTA-(RGDfK-PEG4) of seriation title complex in the lotus naked mouse of U87MG knurl2For title complex of the present invention).
Fig. 6 is18The uptake values of the F mark series different time of title complex in the lotus naked mouse of U87MG knurl in tumour and major organs and corresponding ratio (wherein RGD3:NOTA-(RGDfK-PEG4)2For title complex of the present invention).
Fig. 7 is the present invention18The different time tumour of F marker ligand compound in lotus U87MG knurl nude mouse and major organs uptake values thereof and corresponding knurl/meat, knurl/liver and knurl/kidney ratio.
Fig. 8 is the present invention18The time m-radioactive activity curve of F marker ligand compound in lotus U87MG neurospongioma nude mouse.
Embodiment
The present invention can be made to be illustrated more clearly in below by way of concrete preparation example and embodiment:
One, preparation example:
1) preparation of PEG4-c (RGDfK)
The PEG4 that the Boc (t-Butylcarbamate, tertiary butoxy carbonyl) of 0.5mmol protects is dissolved in 5mLDMF, adds NHS and 0.6mmolDCC of 0.6mmol, at room temperature react 3 hours. 0.4mmolc (RGDfK) (cyclisation rgd peptide) is joined in above-mentioned reaction solution, regulates pH to 8 ~ 8.5 with DIEA, room temperature reaction 8 hours. Reaction solution adds 6mL ammonium acetate buffer (0.5mol/L, pH=7) and filters. Filtrate, with high performance liquid chromatography (HPLC) separation and purification, obtains product B oc-PEG4-c (RGDfK) about 140mg. Target product is confirmed as through mass spectroscopy (theoretical value is 1665.85).
Deprotection: join in 10mgBoc-PEG4-c (RGDfK) with 3mL trifluoroacetic acid, room temperature reaction 30 minutes, revolves and steams removing TFA, and residue is dissolved in 2mL ammonium acetate buffer (0.5mol/L, pH=7). Again with HPLC purifying, collect target product peak and freeze-drying, obtain PEG4-c (RGDfK) about 122mg. Target product is confirmed as through mass spectroscopy (theoretical value is 1565.80).
2) E [PEG4-c (RGDfK)]2Preparation
Being dissolved in 5mLDMF by the L-glutamic acid (E) that 2mmolBoc protects, add 4.2mmolNHS and 4.2mmolDCC, room temperature reaction 10 hours, filter and remove by-product of dicyclohexylurea (DCU), filtrate is spin-dried for and obtains crude product. Dissolving crude product with 3mL methylene dichloride, filter, filtrate is slowly added drop-wise in the ether of 30mL, precipitates out white precipitate, dry product 0.4g, through core magnetic (1H-NMR) expection product B oc-E (OSu) is confirmed as2; By 0.02mmolBoc-E (OSu)2It is dissolved in 2mLDMF solution after mixing with 0.06mmolPEG4-c (RGDfK), regulates pH to 8 ~ 9 with DIEA, room temperature reaction 8 hours. Through HPLC purifying and obtain 32mg white lyophilized powder after freeze-drying. Boc-E [PEG4-c (RGDfK)] is confirmed as through mass spectroscopy (theoretical value is 1912.99)2. With anhydrous TFA remove protecting group, again through HPLC purifying and freeze-drying obtains E [PEG4-c (RGDfK)]2. Through mass spectroscopy (m/z=1811.94 [M+], theoretical value is 1813.0) confirm as target product.
3) NOTA-E [PEG4-c (RGDfK)]2The preparation of (compound 1)
In 20mL reaction flask, add the E [PEG4-c (RGDfK)] that 105.5mg is dissolved in 5.0mLDMSO2(0.058mmol) solution and 20mgNOTA-NHS(0.05mmol) and 0.05mLDIEA, room temperature reaction also monitors reaction process with analysis mode HPLC. After 30 minutes, again add 20mgNOTA-NHS(0.05mmol) and 0.05mLDIEA, it is possible to repeat this process until initial E [PEG4-c (RGDfK)]2Till raw material reaction is complete. Subsequently with 0.25mL acetic acid (being dissolved in 5mL water) termination reaction, and reaction solution is divided into four parts and is prepared type HPLC separation and purification. Collect target compound to evaporate point (Rt=21.6min), after merging, carry out freeze-drying. Obtaining product 96mg, product rate about 78.7%, purity is greater than 97%(analysis mode HPLC, and retention time is 15.5min). Through mass spectroscopy (m/z=1049.74 [(MHH)/2]++, theoretical value is 2097.07) and confirm that product is compound 1:NOTA-E [PEG4-c (RGDfK)]2��
4) HPLC gradient condition
Preparation HPLC: C18 preparative column (PROTO300,5 ��m, 250 �� 20mm, HigginsAnalytical, Inc.). Linear drip washing gradient: 0 ~ 5 minute: 6%A(0.1%TFA acetonitrile solution) and the 94%B(0.1%TFA aqueous solution), 5 ~ 35 minutes: be increased to 65%A and 35%B; Flow velocity: 12mL/min; Compound 1 retention time is 21.6min.
Analysis mode HPLC:C18 analytical column (WatersSymmetry, 5 ��m, 150 �� 3.9mm). Linear drip washing gradient: 0 ~ 5 minute: 5%A(0.1%TFA acetonitrile solution) and the 95%B(0.1%TFA aqueous solution), 5 ~ 35 minutes: be increased to 65%A and 35%B; Flow velocity: 1mL/min; Compound 1 retention time is 15.5min.
Two, Application Example:
1. radioactivity18The preparation (to prepare 100) of F mark freeze drying medicine box
Take 8mg compound 1 to be dissolved in the NaAc_HAc buffer solution (pH4) of 10mL0.5mol/L, then by 0.08mg aluminum chloride (AlCl3) be dissolved in the NaAc_HAc buffer solution (pH4) of 10mL0.5mol/L, will the two Homogeneous phase mixing. Being sub-packed in 100 1.5mLAxygen after sterile filtration without, in wall built-up cryopreservation tube, being then placed in freeze drier lyophilize 24 hours, sealing of jumping a queue, obtains froze-dried kit. According to medicine box output and to the difference often propping up component concentration requirement in medicine box, the consumption of adjustable compound 1 and aluminum chloride, makes their weight ratio drop on (20 ~ 100): in 1 scope.
2.18F marks the preparation of RGD title complex:
1) wet method: each 1.5mLAxygen obtained in step 1 without wall built-up cryopreservation tube in add about 37 ~ 3,700 million shellfishes can (MBq)18F-(accelerator directly obtains target water18O-18F water), it is placed in boiling water bath reaction 15 minutes, namely obtains title complex. Analyze through HPLC it will be seen that radio chemistry product rate is 68.1% after being 62.1%(decay correction), FIGS 1A. Through Sep-PakC18 chromatographic column separation and purification after thin up reaction solution, rinse chromatographic column with water and remove unreacted18F ion, obtains target tagged compound with ethanolic soln drip washing, and after normal saline dilution, namely sterile filtration obtain tagged compound injection liquid. This product is carried out HPLC Analysis and Identification by sampling, and the radiochemical purity after purifying is greater than 99%.
2) lyophilization: the acetic acid-acetate buffer (pH4) adding 0.5mL0.5mol/L in froze-dried kit step 1 obtained, adding about 37 ~ 3,700 million shellfishes after all dissolving can (MBq)18F-(accelerator directly obtains target water18O water), airtight 80 ~ 120 �� of C react 5 ~ 15min, cooling; Through Sep-PakC18 chromatographic column separation and purification after thin up reaction solution, rinse chromatographic column with 0.5mol/L phosphate buffered saline buffer (pH7.4) and remove unreacted18F ion, obtains target compound with ethanol solution hydrochloride drip washing, and after normal saline dilution, namely sterile filtration obtain tagged compound injection liquid. This product is carried out HPLC Analysis and Identification by sampling, and the radiochemical purity after purifying is greater than 99%.
Hereinafter the performance measurement of RGD part and the RGD title complex of radioactivity Value linear mark thereof is described:
1.NOTA-E [PEG4-c (RGDfK)]2(compound 1) and integrin receptor ��v��3Avidity measure
Adopt cell competition Binding experiment method, measure ligand compound 1 of the present invention, known compound (c (RGDfK) respectively2), with reference to compound (NOTA-c (RGDfK)2) and NOTA-PEG2-c (RGDfK)2) with human glioma cell U87MG express integrin receptor ��v��3Protein binding ability, test with125I-Echistatin is as acceptor ��v��3The radioactive ligand that protein-specific combines. Experimental result shows: all parts containing RGD structural unit and acceptor ��v��3Albumen all has higher avidity, the compounds of this invention 1(NOTA-E (FK-PEG4)2) 503nhibiting concentration be 127.93nM, other known compound or be Wei 200.49nM(c (RGDfK) with reference to the 503nhibiting concentration of compound2), 513.63nM(NOTA-c (RGDfK)2) and 393.85nM(NOTA-PEG2-c (RGDfK)2). To transform the 503nhibiting concentration of rear RGD part minimum in the present invention as can be seen here, and namely avidity is the highest, is better than part that is that do not transform or the transformation of other form. The results detailed in accompanying drawing 2.
2.HPLC Analysis and Identification
HPLC system is as follows: anti-phase C18 analytical column (4.6 �� 250mm), drip washing gradient: 0 ~ 5 minute: 5% acetonitrile (0.1%TFA) and 95% water (0.1%TFA) remain unchanged; 5 ~ 35 minutes: being increased to 65% acetonitrile (0.1%TFA) and 35% water (0.1%TFA), flow velocity is 1mL/min, and radio-labeling title complex retention time is about 17min, and calculates radiochemical purity with this and be greater than 99%. HPLC the results are shown in accompanying drawing 1B.
3.18The vitro stability of F marker ligand compound measures
The above-mentioned radiochemical purity obtained by embodiment be greater than 99%18The ethanolic soln of F marker ligand compound. Carrying out HPLC Analysis and Identification before and after ethanol is removed respectively, method is the same. And it is similar with known18F marker ligand compound ([18F] AlF-NOTA-PRGD2, structural representation FIGS 3A) contrast. Result shows: the present invention18F marker ligand compound remove before and after ethanol all can stable existence, its outward appearance and radiochemical purity are without considerable change (removing the FIGS 1B and Fig. 1 C respectively of the HPLC analytical results before and after ethanol). And known title complex [18F] AlF-NOTA-PRGD2 has after ethanol obviously assorted peak to occur (removing the FIGS 3B and Fig. 3 C respectively of the HPLC analytical results before and after ethanol) removing, it is seen that and title complex of the present invention has better stability.
4.18The bio distribution of F marker ligand compound in tumor bearing nude mice body
Prepare radiochemical purity by embodiment and it is greater than 99%18F marks complex solution. It is about 3.7MBq from the tail vein injection 0.1mL(of the lotus naked mouse of U87MG knurl (body weight about 20 grams)) tagged compound injection liquid, then after administration 60 minutes to sacrifice, get the tissue such as its blood, the heart, liver, lung, kidney, muscle, pancreas, bone, spleen, stomach, intestines and knurl to carry out weighing and measure radiocounting, calculate hundred points of injections dose rate (%ID/g) of per gram of tissue. In order to verify the specificity of tumor uptake, within 10 minutes, inject unlabelled compound 1 in advance, again carry out biodistribution experiments. The results are shown in accompanying drawing 4. It thus is seen that tagged compound of the present invention absorbs higher in tumour, and can obviously being suppressed, illustrate that tagged compound of the present invention is the tumor developer of specificity, the picked-up of non-target background is lower, it is possible to for tumor imaging.
5. tumor model mouse MicroPET develops
1) prepare radiochemical purity by embodiment and it is greater than 99%18F marks complex solution, gets 0.1mL(and is about 3.7MBq) it is injected in the lotus naked mouse of U87MG knurl (body weight about 20 grams) tail vein, and after carrying out dynamic PET image collection to administration immediately 60 minutes. MicroPET is scanned gained whole body decay correction crown image drawing district interested (ROI). Obtaining the radioactive activity in the organs such as tumour, muscle, liver, kidney and urine from multiple ROI average pixel value and be converted into MBq/mL, gained value obtains %ID/g(divided by injected dose and supposes that tissue density is 1g/mL). Image results figure and dynamic time-radioactive activity curve are shown in accompanying drawing 5,6,7 and 8. It thus is seen that tagged compound of the present invention has obvious picked-up in tumour, and can significantly be suppressed. Within about 10 minutes, reach maximum value upon administration, there is no thereafter considerable change. And absorb in urinating and progressively increase, it is possible to because this compound is caused by kidney metabolism.
2) same to 1) under condition, other is similar18F marker ligand compound (RGD1:NOTA-RGDyK2; RGD2:NOTA-RGDfK2; RGD4:NOTA-PEG3-RGDyK2; RGD5:NOTA-PEG4-RGDfK2) carry out MicroPET development and compare with the compounds of this invention (RGD3:NOTA-(RGDfK-PEG4) 2). Image results FIGS 5 and 6. It thus is seen that absorb higher in tumour through the compounds of this invention 1 of radio-labeling, and it is detained best, it is possible to be used for carrying out tumor imaging, for the diagnosis of tumour, curative effect and prognostic evaluation provide foundation.
Compound 1 and18F marker ligand compound is a kind of new radio-labeling RGD title complex that the present inventor develops, compared with existing conventional tumor developer, and itself and tumour integrin receptor ��v��3Protein affinity height, high specificity, it is possible to carry out live body without wound tumor imaging. Radiolabeled complexes preparation process of the present invention is very easy after medicine box, and particularly radioactivity product rate height, price are cheaply advantageously applied in clinically.
The present invention's radionuclide used can also comprise64Cu��68The nucleic such as Ga, other more how optional radionuclide comprises and being not limited to62Cu��67Cu��89Zr etc., preparation method is similar.
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| CN107474145B (en) * | 2017-09-15 | 2020-09-15 | 中国工程物理研究院核物理与化学研究所 | RGD peptide-serum protein binding fragment conjugate, preparation method thereof, radionuclide marker and application |
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| CN113402579A (en) * | 2021-06-22 | 2021-09-17 | 中南大学湘雅三医院 | Radioisotope-labeled polypeptide for tumor imaging |
| CN116333037A (en) * | 2021-12-17 | 2023-06-27 | 化学与精细化工广东省实验室 | Thiol-containing peptides and fluoroporphyrins coupled as biological probes |
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Effective date of registration: 20170713 Address after: Rugao City, Jiangsu province 226532 Nantong town mayor Yuejiang Road No. 38 Patentee after: Nantong Kaiyuan Pharmaceutical Chemical Co.,Ltd. Address before: 225400 No. 10-2 South Xingang Road, Taixing Economic Development Zone, Taizhou, Jiangsu Patentee before: JIANGSU SHIMEIKANG PHARMACEUTICAL Co.,Ltd. |
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Address after: 226532 No. 38, Yue Jiang Road, Changjiang Town, Rugao, Nantong, Jiangsu Patentee after: JIANGSU XINRUI PHARMACEUTICAL Co.,Ltd. Address before: 226532 No. 38, Yue Jiang Road, Changjiang Town, Rugao, Nantong, Jiangsu Patentee before: Nantong Kaiyuan Pharmaceutical Chemical Co.,Ltd. |
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Effective date of registration: 20240311 Address after: No. 101, Building 52, 500 Binhai East Road, Muping District, Yantai City, Shandong Province, China, 264000 yuan Patentee after: Yantai Lannacheng Biotechnology Co.,Ltd. Country or region after: China Address before: 226532 No. 7, Yue Jiang Road, Changjiang Town, Rugao, Nantong, Jiangsu Patentee before: JIANGSU XINRUI PHARMACEUTICAL Co.,Ltd. Country or region before: China |
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Address after: No. 101, Building 52, 500 Binhai East Road, Muping District, Yantai City, Shandong Province, China, 264000 yuan Patentee after: Yantai Lannacheng Biotechnology Co.,Ltd. Country or region after: China Address before: No. 101, Building 52, 500 Binhai East Road, Muping District, Yantai City, Shandong Province, China, 264000 yuan Patentee before: Yantai Lannacheng Biotechnology Co.,Ltd. Country or region before: China |
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